Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer disease are a susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in patients with Alzheimer disease will affect pain processing. Here, we leverage animal behavior, neural activity recording, optogenetics, chemogenetics, and Alzheimer disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to pain response. The 53 familial Alzheimer disease mice show alleviated mechanical allodynia which can be regained by the genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation, as well as the dendritic spine reduction of ACC pyramidal neurons in 53familial Alzheimer disease mice can be mimicked by Rac1 or actin polymerization inhibitor in wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.

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Background: Neuroinflammation is one of the most important contributing factors for the pathogenesis of Alzheimer’s disease (AD). Cyclooxygenase-1 (COX-1) is distinctly expressed in microglia and involved in microglia activation and neuroinflammation in the AD. However, the molecular mechanisms by which COX-1 regulated microglia activation and participated in AD progression remains unclear. This study was designed to investigate the cellular and molecular mechanisms underlying COX-1 regulation of neuroinflammation. Methods: C57BL/6J, 5×FAD and 5×FAD/COX-1 knockout (KO) mice of different ages (e.g. 3-month-old, 6-month-old, 9-month-old) were used. Motor function and cognitive ability were evaluated using the open field test, novel-object recognition test and Morris water maze tests. The deposition of amyloid beta (Aβ) was examined by Thioflavin-S fluorescence, and neuroinflammation was investigated by immunohistochemistry, immunofluorescence and immunoblotting. Results: Konock out (KO) of COX-1 improved cognitive impairment and motor deficits, and reduced the accumulation of Aβ plaques in the cerebral cortex and hippocampus. COX-1 KO promoted microglia transition from M1 to M2 status, and reduced NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome. This was mediated by the inhibition of prostaglandin E2 (PGE2)/EP2 pathway and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-nuclear factor-κB (NFκB) p65 axis. Conclusions: COX-1 may contribute to the impairment of clearance Aβ and exacerbation of neuroinflammation which led to cognitive deficits in 5×FAD transgenic mice. The effects of COX-1 were mediated through PGE2/EP2 pathway which activated cAMP-PKA-NFκB p65 axis and NLRP3 inflammasome. The results suggest that the inhibition of COX-1 may be a potential pharmacological approach for the treatment of AD.

It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signaling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. The cognitive ability was assessed by novel object recognition task (NORT) and Morris water maze (MWM) test. Immunofluorescence, Golgi-cox staining were used to observe dendritic synaptic. Gamma oscillation in hippocampus CA1 was performed by Tetrode in-vivo recording. Prostaglandins were measured by HPLC/mass spectrometry. We observed the expressions of cAMP/ BDNF pathway proteins in hippocampus and N2a cells by Elisa and western blot. We found COX-2 gene knockout could significantly impact the learning and memory ability; reduce the expression of PSD95 in the neuron; cause synaptic disorder; influence gamma oscillation and reduce the expression PGE2, cAMP, p-PKA, p-CREB and BDNF in the hippocampus. It suggests COX-2 may play a critical role in learning and memory ability in modulating postsynaptic membrane PSD95, regulating synaptic plasticity and gamma oscillation in the hippocampus CA1 by regulating COX-2/BDNF signaling pathway.